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Current Cancer Drug Targets, 2020, 20, 729-740

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journal for 1 130 320 465 585 688 722 750- (a) 850 The Roles of Alternative Splicing in Tumor-immune Cell Interactions CC timely indepth

N- N- Reviews & Research (d) (b) on Drug

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Cancer

BENTHAM SCIENCE

Yue Wang1,2, Honglei Zhang2,3,*, Baowei Jiao2,4,5,*, Jianyun Nie1,6,*, Xiyin Li1,2, Wenhuan Wang1 and Hairui Wang1,2

1Third Affiliated Hospital of Kunming Medical University, Kunming 650118, China; 2State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; 3Yunnan University of Chinese Medicine, Kunming 650500, China; 4KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China; 5Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China; 6Department of Breast Cancer, Third Affiliated Hospital, Kunming Medical University, Kunming 650118, China Abstract: Alternative splicing (AS) plays a significant role in the hallmarks of cancer and can pro- A R T I C L E H I S T O R Y vide neoantigens for immunotherapy. Here, we summarize recent advances in immune system asso- ciated tumor specific-antigens (TSAs) produced by AS. We further discuss the regulating mecha- Received: January 30, 2020 Revised: May 09, 2020 nisms involved in AS-mediated innate and adaptive immune responses and the anti-tumoral and pro- Accepted: May 11, 2020 tumoral roles in different types of cancer. For example, ULBP1_RI, MLL521spe, NKp44-15,

DOI: MHC-I7, CD200S1, 2, PVR α/β/γ/δ and IL-33 variants 1/2/3 act as regulators in solid tumors and 10.2174/1568009620666200619123725 IPAK4-L and, FOXP1ΔN100 exhibit functions in hematological cancers.

Keywords: Alternative splicing, tumor cells, immune system, immunotherapy, neoantigens, Tumor specific-antigens (TSAs). 1. INTRODUCTION more than 90% of human coding genes [9]. Introns and ex- ons are selectively included or excluded in the AS process Immunotherapy has transformed the treatment of many [10]. Therefore, pre-mRNAs are modified into various advanced cancers [1]. Immunotherapeutic anticancer ap- isoforms and then translated into proteins during AS, in or- proaches, such as therapeutic vaccines and T cell receptor der to meet cell diversity demands [11]. Previous studies engineered T cells (TCR-T cells), rely heavily on suitable have identified and categorized five types of AS events, in- target antigens [2]. Currently, there are three main types of cluding exon skipping (SE), intron retention (RI), alternative tumor antigens: i.e. antigens derived from tumor-specific 3’ splice site (A3SS), alternative 5’ splice site (A5SS), and somatic mutation, cancer germline antigens (CGAs), and mutually exclusive exon (MXE) events [12]. In addition, AS antigens derived from viral genes expressed by viral-infected regulates most hallmarks of cancer, including proliferation, tumor cells. Clinical studies have shown remarkable out- apoptosis, hypoxia, angiogenesis, immune escape and metas- comes in cancer patients receiving either TCR-T cell therapy tasis [13-15]. Following the rapid development of sequenc- targeting CGAs [3, 4] or neoantigen-based vaccines [5-7]. ing technology, various studies have shown that cancer- Neoantigens are tumor-specific antigens (TSAs) that do not specific AS can produce neoantigens. For example, Jaya- exist in normal human genomes. In non-virus-related tumors, singhe et al. analyzed 8 656 tumor samples and found that neoantigens are derived from novel protein sequences splice-site-creating mutations can produce more neoantigens formed by tumor-specific DNA damage. For virus-related than other types of mutations [16]. Hoyos et al. also reported tumors, such as cervical cancer, neoantigens can also come that tumor-specific splicing has the potential to generate a from viral open reading frames [8]. The major obstacle for large new class of tumor-specific neoantigens [17]. From the broader applicability of tumor immunotherapies is the another perspective, for cancers that exhibit low prevalence lack of targetable neoantigens for many cancer types. of somatic mutations and copy number variations but wide- To date, mutation-derived neoantigens have received spread mRNA splicing aberrations (e.g., B cell acute lym- considerable attention, with neoepitopes derived from phoblastic leukemia), the expanded target scope of immuno- mRNA processing events. Alternative splicing (AS) is a reg- therapies may lead to more efficient development [18]. Thus, ulated process that occurs during gene expression. It results AS-derived neoantigens may offer a much broader scope for in a single gene coding for multiple proteins and affects immunotherapy applications. The human immune system, which includes innate and *Address correspondence to these authors at Kunming Institute of Zoology, adaptive immunity, is a host defense system comprised of Chinese Academy of Sciences; 32 Jiaochang E. Road, Kunming, Yunnan, biological structures and processes that protect against disease China; Tel: +86-871-68191706; E-mail: [email protected]; jiaobao- [19]. Neoantigens from tumor cells affect the efficacy of both [email protected] and Department of Breast Cancer, Third Affiliated Hospital, Kunming Medical University, 519 Kunzhou Road, Kunming, the innate and adaptive immune systems. In neoantigen- Yunnan, China; Tel: +86-13608815577; E-mail: [email protected] expressing tumors, natural killer (NK) cell stimulation can

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Table 1. Role of alternative splicing (AS) in human tumor immunity.

Immune Splice Splicing Splice Patterns Role Study Type Reported Effect Refs. Type Isoform Regulator

Tumor cells escape NK ATF4 Pro- Tumor-derived human cell cell surveillance by Innate ULBP1_RI [38, 39] RBM4 tumoral line-HAP1 cells increasing ULBP1_RI isoform RI

SE Normal tissues; Human melanoma cells NKp44 binds with Not men- Anti- (WM1361); Innate MLL521spe MLL521spe to activate [54, 55] tioned tumoral Human lung adenocarci- NK cells noma cells (H441); Mouse EL4 cells

SE HeLa cells; Cytokine Breast cancer cells NKp44-15 binds with Pro- [48, 52, Innate NKp44-15 (IL-15, IL- (MCF7); PCNA to inhibit NK cell tumoral 53] 18, TGF-β) Human melanoma cells lysis (A375)

Full-length Mutation of U2AF1 leading to IRAK4-L Pro- AML; Innate IPAK4-L U2AF1 isoform production and [58] tumoral Normal hematopoietic cells innate immunity activa- tion.

SE MHC-I7 is recognized Not men- Anti- Melanoma treatment by TCR, inducing Adaptive MHC-I7 [68] tioned tumoral model of C57BL/6 stronger anti-tumor immune responses

SE Human carcinoma tissues; CD200S activates Rat C6 glioma cell lines; Not men- Anti- CD8+T cells, CD200L Adaptive CD200S1,2 Glioma rat model; [76-78] tioned tumoral induces immunosuppres- Wistar rats model with lung sive response metastasis

SE Transmembrane PVR ATF6 Anti- Hepatocellular (PVR α, δ) activates PVR α, δ tumoral carcinoma (HCC) cells CTLs by binding to CD226 [84, 86, Adaptive SE Soluble isoform (PVR β, 89, 91] γ) suppresses CTLs by Pro- PVR β, γ IFNγ Melanoma cells increasing expression of tumoral inhibitory receptor TIG- IT

SE CRC cells; IL-33 variant Not men- Dual IL-33 promotes or inhib- [94- Adaptive NSCLC cells; 1/2/3 tioned effect its tumorigenesis. 101] Breast cancer cells

SE DLBCL cells; FOXP1ΔN100 can activate Not men- Pro- 104, Adaptive FOXP1ΔN100 human B cells; B cells and lead to de- tioned tumoral [105] Mouse lymphoma models velopment of DLBCL.

represents splice pattern corresponding to splice isoform on left column. ‘New’ aindicates new insert sequence. RI: intron retention; SE: exon skipping; ATF: activating transcription factor; MLL5: mixed-lineage leukemia-5; spe: special; NK cell: natural killer cell; MHC: major histocompatibility complex; CD200S: truncated forms of CD200; CD200L: full-length CD200; TIGIT: T cell Ig and ITIM domain; PVR: poliovirus receptor; IFN γ: interferon γ; CTLs: cytotoxic T lymphocytes. DLBCL: diffuse large B cell lymphoma; U2AF1: U2 small nuclear RNA auxiliary factor 1; IRAK4-L: long isoform of interleukin-1 receptor- associated kinase 4; CRC: colorectal cancer; NSCLC: non-small cell lung cancer; HCC cell: hepatocellular carcinoma. enhance the number and function of tumor-specific T cells, AS events and corresponding functions are summarized causing tumor growth inhibition [20]. Here, to characterize in Table 1. All illustrations were created using Adobe Illus- the roles of AS in tumor-immune interactions, we catego- trator CS6. rized them into innate and adaptive immunity contexts. The Roles of Alternative Splicing in Tumor-immune Cell Interactions Current Cancer Drug Targets, 2020, Vol. 20, No. 10 731

Innate Immunity Tumor cell ULBP1 ↓ RBM4 ↓ ULBP1_RI ↑ NK cells inhibited Nucleus Tumor growth ↑

HLA-1 bit PCNA △21spe th ↑ e MLL5 NK cells activated NKG2D △5 NKp44-1 Tumor growth ↓ m lsls o r NKp44 NKp44 NK cell ted ligand h ↓

NKp44 MLL5 Nucleus

Normal cell

Fig. (1). Schematic of AS between innate immunity and tumor cells. Red and green dotted lines represent inhibition and activation of NK cells, respectively.↑ represents promoted tumor growth, ↓ represents inhibited tumor growth or downregulation of RBM4. Tumor cells down- regulate RBM4 and subsequently increase ULBP1_RI. ULBP1 is an NKG2D ligand on tumor cell surface, and is recognized by NKG2D on the surface of NK cells, which are then activated. ULBP1_RI and ULBP1 combine competitively with NKG2D, and ULBP1_RI functions as a negative regulator of NK cells. Green: in normal cells, MLL5 protein is in the nucleus. In the tumor environment, abnormal isoform of MLL5 (MLL521spe) is highly expressed on cell surface, and activates NKp44+ NK cells. NK cells are activated by combination of NKp44 and corresponding ligand located in normal membrane. NK cells expressing alternative NKp44 isoform (NKp44-15) can be inhibited by proliferating cell nuclear antigen (PCNA) ligands, which are often highly expressed on tumor cell surface. (A higher resolution / colour ver- sion of this figure is available in the electronic copy of the article).

2. AS AND TUMOR INNATE IMMUNE RESPONSES ligands expressed by potential target cells [30, 31]. One of the best-studied NK-activating receptors is NKG2D, which Innate immune cells, including macrophages, dendritic is also expressed in certain T cell subsets [32]. NKG2D lig- cells (DC), and NK cells, contribute to spontaneous and ands are often highly expressed in tumor cells (such as mela- acute antitumor responses by releasing mediators of inflam- noma), but not in normal cells [33]. The structure of NKG2D mation, such as cytokines and chemokines, which activate ligands is similar to that of the MHC- protein. Humans and recruit local immune cells [21]. NK cells have received have eight NKG2D ligands, whereas mice have 5_6 different renewed interest recently as they do not rely on antigen spec- ligands [34]. As a human NKG2D ligand, ULBP1 has two ificity and can directly kill malignant or transformed cells by isoforms: i.e., ULBP1 and ULBP1_RI (intron-retained iso- releasing cytotoxic granules [22]. NK cells also exhibit the form) (Table 1) [35]. The relative expression between these capacity to preferentially kill cancer stem-like cells [23]. two isoforms confers the level of NK cell activation. High Several studies have successfully exploited NK cell func- ULBP1 expression is associated with elevated NK activa- tions against neuroblastoma [24, 25], glioblastoma [26, 27], tion, whereas ULBP1_RI corresponds to the deactivation of and lung cancer [28]. Lacking antigen-specific receptors, NK NK cells. Both RBM4 and ATF4 are regulators of ULBP1 cells use a set of innate receptors to sense and respond to expression: AFT4 directly binds to the promoter of ULBP1 changes in the tumor-immune microenvironment. Specifical- to promote transcriptional activation, whereas RBM4 inhibits ly, activated receptors (e.g., NKG2D and natural cytotoxicity the formation of splicing isomer ULBP1_RI [36]. Tumor receptors (NCRs)) and inhibited receptors (e.g., major histo- cells can escape NK cell surveillance by decreasing the ex- compatibility complex, MHC-I) on the surface of NK cells pression of RBM4, resulting in lower and higher expression are in a state of dynamic balance, which determines the func- of ULBP1 and ULBP1_RI, respectively [35]. Yong et al. tional state of these cells [29]. Given the ability of NK cells found that low expression of RBM4 is associated with poor to detect and destroy a range of cancerous tissues, mechanis- prognosis in gastric cancer [37] and is mediated by control- tic insight into how cancer cells regulate NK cell activity at ling cancer-related splicing [36]. the AS level and the pharmacological modulation of these activities represent an underexplored potential in immuno- The ULBP ligand family contains ULBP1, ULBP2, therapy. The splicing events involved in innate immunity are ULBP3, and RAET1E. RAET1E can be transformed into a illustrated in Fig. (1). truncated and soluble form by AS, termed RAET1E2, which is found in many human cancer cell lines, such as liver car- cinoma, gastric adenocarcinoma, and ovarian carcinoma 2.1. NK Cells in Solid Tumors [38]. RAET1E2 can also inhibit NKG2D-mediated NK cyto- 2.1.1. Tumor Cells Escape NK Cell Surveillance by In- toxicity resulting in an immune escape mechanism in tumors creasing Expression of ULBP1_RI Isoform [38]. Although the innate immune system has become an area of intense interest in immunotherapy, the mechanisms NK cells are regulated by a balance of signals from acti- involved in the enhancement of NK cell capacity to inhibit or vating and inhibitory receptors, which recognize cognate kill tumor cells need further exploration. 732 Current Cancer Drug Targets, 2020, Vol. 20, No. 10 Wang et al.

2.1.2. NKp44 and NKp44-15 Function as Positive and the NKp44-15-PCNA sites represent potential approaches Negative Regulators of NK Cells, Respectively for cancer immunotherapies. NK cells are activated by various receptors, including the NCR family, which is comprised of NKp46 (NCR1, 2.2. Innate Immune Pathways in Hematological Cancers CD335), NKp44 (NCR2, CD336), and NKp30 (NCR3, Spliceosome mutations in myeloid malignancies, such as CD337) [39]. NKp44 is encoded by the NCR2 gene located AML, are a form of oncogenic mutation. A recent study on on chromosome 6 in the human MHC class II locus and is AML samples found that mutant U2 small nuclear RNA aux- exclusively expressed in activated NK cells [40, 41]. NKp44 iliary factor 1 (U2AF1) induces an exon 4-contained AS expression is associated with a marked increase in cytolytic isoform of interleukin-1 receptor-associated kinase 4 activity in NK cells [42, 43]. In addition, non-covalent bind- (IRAK4), which encodes the IRAK4-L protein, to activate ing with DAP-12 is essential for NKp44-mediated NK acti- innate immunity [53]. IRAK4 activates the NF-κB and vation [44]. MAPK pathways via the mediation of downstream signaling Recent research has revealed that AS can occur during of the Toll-like receptor (TLR) superfamily [54]. IRAK4 can transcription of the NCR2 gene, resulting in transcripts that be divided into two spliced isoforms depending on whether encode receptor isoforms with inhibitory functions. For ex- exon 4 is contained or excluded: i.e., IRAK4-L and IRAK4- ample, the alternative isoform of NKp44 that lacks exon 5 S (Table 1) [53]. IRAK4-S can control innate immune re- (NKp44-15) can inhibit NK cell activation, which is trig- sponses in normal hematopoietic cells, whereas IRAK4-L gered by proliferating cell nuclear antigen (PCNA) (Table 1) mediates NF-κB maximal activation, resulting in uncon- [45]. PCNA is an inhibitory ligand of higher NKp44 expres- trolled innate immune responses in malignant hematopoietic sion found on the surface of tumor cells [46] and interacts cells [55]. IRAK4-L also exhibits high expression in breast with the NKp44-15 isoform. Mechanically, in the presence and colon cancer cells, indicating an association with onco- of NKp44-15, PCNA in tumor cells is presented by human genicity [53]. Furthermore, mutant U2AF1 (S34F) AML histocompatibility leukocyte antigen-1 (HLA-1) and is then cells acquire a dependency on IRAK4-L and are sensitive to recruited to the NK immunological synapses (NKIS), which, IRAK4 inhibitors, suggesting potential therapeutic strategies in turn, induce an inhibitory effect on NK cells [47]. [53]. The expression of NKp44-15 can be affected by cyto- kines, such as IL-15, IL-18, and TGF-β [48]. IL-15 improves 3. AS AND TUMOR ADAPTIVE IMMUNE RESPONSE NKp44-15 levels, whereas IL-18 plays a role in its down- 5 Adaptive immunity can be divided into T cell-mediated regulation [48]. NKp44-1 also contributes to a shift in pe- cytotoxic responses and B-cell-mediated antibody responses. ripheral blood NK cells towards decidua basalis NK [48]. The proliferation of primary T cells can be activated by a Shemesh et al. found that NKp44-1 expression is significant- specific combination of TCRs and MHC on the surface of ly associated with poorer survival in acute myeloid leukemia antigen-presenting cells (APCs) [56]. MHC restriction in (AML) patients [49]. In addition, overexpression of NKp44- antigen recognition means that CD4+ T cells recognize MHC 1 in NK-92 cells can reverse the inhibitory effect of NK-92 class II molecules and CD8+ T cells recognize MHC class I cells on PCNA mediation, leading to poor lytic immune syn- molecules [57]. For B cell-mediated adaptive immunity apse formation [49]. (known as humoral immunity), when pathogens and antigens NKp44-mediated NK cell activation is also regulated by enter the body, specific B cells are induced to differentiate mixed-lineage leukemia-5 (MLL521spe) although MLL5 is into plasma cells and antibodies and antigens are produced to not the major ligand of NKp44 [50]. MLL5 21spe lacks an prevent pathogenic infection [58]. Memory cells are also exon 21spe at the C-terminus and encodes a highly con- produced when the primary immune response is activated. served 1168-amino acid protein (Table 1). This specific When the same antigen reappears, the memory cells respond 21spe fragment was previously reported in GenBank (acces- quickly to produce a powerful counterattack [59]. The splic- sion no. AAR13894.1). In normal cells, MLL5 is specifically ing events involved in adaptive immunity are illustrated in expressed in the nucleus, whereas MLL521spe is located on Fig. (2). the tumor cell surface and is recognized by NKp44 [51]. 21spe Therefore, NK cells can recognize the MLL5 isoform 3.1. T Cells in Solid Tumors on the tumor cell surface and thus activated to eliminate these cells. 3.1.1. MHC-I7-expressing DCs Present Antigen More Ef- Other MLL5 isoforms such as MLL5β reported in human ficiently and Easily than Normal DCs papillomavirus induced cervical cancer, function as im- As APCs, DCs with MHC-I on the membrane surface portant active regulators of oncogene E6 and E7 transcrip- play important roles in activating T lymphocytes [60]. The tion [52]. Full-length MLL5 is comprised of 25 exons, function of MHC-I is mainly determined by the highly con- whereas MLL5β is truncated at exon 14 due to the insertion 21spe served amino acid sequence in its cytoplasmic tail encoded of 26 nucleotides [52]. MLL5 functions differently from by exons 6 and 7 [61]. Deletion of the cytoplasmic tail re- MLL5β because of its unique subcellular localization on the sults in reduced function or even loss of MHC-I [62]. How- cell-surface. ever, the exon 7-deleted splice variant of MHC-I (MHC-I7) Taken together, in the battle between NK and tumor is still capable of presenting internal and external antigens cells, AS plays a critical role in the activation of NKp44- and has a remarkable antigen-presenting ability, which can + mediated NK cell response. Thus, providing additional be recognized by the TCRs of CD8 T cells and can induce MLL521spe isoforms or designing molecules to compete with stronger anti-tumor immunity (Table 1) [63]. Mechanically, The Roles of Alternative Splicing in Tumor-immune Cell Interactions Current Cancer Drug Targets, 2020, Vol. 20, No. 10 733

CD200L Adaptive immunity Tumor cell α δ CD200R CD86- TAM T cells inhibited TM TM β γ Tumor growth ↑ tmPVR CD200S

CD200R sPVR CD86 CD86+ TAM T cells activated TIGIT Tumor growth ↓

CD226 CD8+T cell DC h ↓ △7 MHC-1 TCR

Fig. (2). Schematic of AS between adaptive immunity and tumor cells. Red and green dotted lines represent inhibition and activation of CD8+T cells, respectively.↑represents promoted tumor growth, ↓represents inhibited tumor growth. Three molecular mechanisms are in- volved. First, two CD200 isoforms, i.e., CD200L and CD200s, function as CD8+ T cell inhibitory and stimulatory regulators. Combination of full-length CD200 (CD200L) and CD200 receptor (CD200R) expressed on CD86 tumor-associated macrophages (TAMs) leads to inhibition of CD8+ T cells. The truncated form of CD200 (CD200S), with exon 1 and 2 deleted, endows TAMs with DC-like morphology, resulting in increased expression of CD86, a co-stimulatory factor, and thus activation of CD8+ T cells. Second, the poliovirus receptor (PVR) has four AS isoforms: i.e., α, β, γ, and δ. PVRα and PVRδ are transmembrane PVRs (tm PVR), which locate and activate the immune response by binding to CD226; the remaining isoforms are soluble PVRs (sPVR), which lack a transmembrane domain and inhibit cytotoxic T lympho- cyte (CTL) anti-tumor immune responses. Finally, exon 7-deleted splice variant of MHC-I (MHC-I7) endows APCs with superior capacity in antigen-presentation, and interact with TCR more efficiently, thus inducing CD8+ T cells to produce a stronger anti-tumor immune re- sponse. MHC-I7 also prompts APCs to secrete more cytokines to stimulate CD8+ T cells. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

MHC-I7 not only improves the bioavailability of presented binding to its receptor (CD200R) [69]. Tumor cells express antigen peptides, but also induces the release of cytokines, two CD200 isoforms, including full-length CD200 such as IFN-γ, when the concentration of antigen peptides is (CD200L) and a truncated form of CD200 (CD200S), which extremely low [63]. occur due to frame-shift mutations during exon 2 and 3 splic- 7 ing and the emergence of termination codons (Table 1) [70]. This superior property of MHC-I has been applied to DC-based anti-tumor vaccines, which effectively extend CD200L expression in mouse tumor cells inhibits activation of tumor-specific T cells, whereas CD200S can release the survival in the B16 melanoma tumor mouse model [63-65]. CD200-CD200R inhibitory interaction and reverse the inhib- These results suggest that the MHC- I cytoplasmic tail en- itory state of immune cells [71]. Tumor-associated macro- coded by exon 7 could be targeted directly in DC vaccines phages (TAMs) isolated from CD200S-enriched C6 tumor [66], which may improve their ability to stimulate the cyto- cells exhibit higher-level expression of MHC IIα and CD11c, toxic T lymphocyte (CTL) response and enhance anti-tumor immunity. resulting in the activation of CD8+T cells [70]. Glioma mod- el rats transplanted with CD200S cells survive for longer The human leukocyte antigen-G (HLA-G) in melanoma periods than those transplanted with CD200L [70]. In addi- cells is also regulated at the mRNA splicing level and can tion, CD200S endows CD200R+ TAMs with DC-like mor- boost anti-tumoral immunity [67]. Melanoma cells can rapid- phology and activates CD8+ CTLs [70]. ly switch cell-surface-located HLA-G1 to intra-cellular HLA-G2, which can restore tumor sensitivity to NK lysis CD200S can also activate the anti-tumor immune re- sponse in a novel type of lung metastasis in Wistar rats, lead- [67]. HLA-G1 is a full-length HLA-G isoform, whereas ing to an effective reduction in lung metastasis [72]. Next- HLA-G2 is a splicing isoform lacking an exon 3α2 domain generation sequencing has also shown that the expression [68]. Therefore, modulating HLA splicing isoforms may be levels of chemokines and granzyme B in CD200S-rich tu- an efficient way in which to boost tumor immunity. mors are much higher than those in CD200-L tumors [72]. 3.1.2. CD200S can Activate CD8+ T Cells and, CD200L can Notably, CD200S promotes enrichment of multiple DC sub- Induce Immunosuppressive Responses sets expressing CD11c, MHC II, CD8, and/or CD103 in tu- mors [72]. This provides an attractive cancer therapy mecha- CD200 is a transmembrane protein expressed in a large nism to reverse the immunosuppressive state by targeting range of tissues, including lymphoid cells, neurons, and en- CD200L or enforcing the CD200S isoform. dothelial, and mainly functions in immune recognition by 734 Current Cancer Drug Targets, 2020, Vol. 20, No. 10 Wang et al.

Pro-tumor IL-33 IL-33 Anti-tumor

Lung Cancer Lung Cancer Migration ↑ MHC-I ↑ Invasiveness ↑ Anti-tumor immune ↑ Tumor growth ↓

CRC Proliferation ↑ CRC Tumorigenesis ↑ Breast Cancer IFN-γ-mediated Metastasis ↑ Breast Cancer anti-tumor immune↑ Tumor growth ↑ Tumor growth ↓ Metastasis ↑ Tumor growth ↓ Metastasis ↓ Stemness ↑ Metastasis ↓ Endocrine resistance ↑

Fig. (3). Opposite functions of IL-33 in tumors. For example, in lung cancer, CRC, and breast cancer, as shown on left, IL-33 can promote tumorigenesis, invasion, metastasis, and drug resistance. On the right, IL-33 inhibits tumors by enhancing the anti-tumor immune response mediated by MHC-1 or IFN-γ. CRC: colorectal cancer. Drugs including FR901464 (SSA), meayamycin B targeting SF3B1, isoginkgetin and 1, 4-heterocyclic, which are involved in step 1 and step 2 splicing [10]. Thus, manipulating AS is a promising immunotherapeutic target with potential research value. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

3.1.3. Transmembrane-located Poliovirus Receptor (PVR) 3.1.4. Dual Effect of IL-33 in Tumor Immunity Activates CTLs by Binding to CD226, Whereas Soluble Isoform Suppresses CTL Immunity Interleukin-33 (IL-33) is a damage-associated molecular pattern (DAMP) molecule belonging to the atypical IL-1 Human PVR is a transmembrane glycoprotein belonging family. In addition to playing an important role in tissue to the immunoglobulin superfamily [73]. Recently, PVR has damage, allergy, infection, and immunity, it is also involved attracted growing attention due to its broad involvement in in pleiotropic immunomodulatory regulation [86, 87]. cancer, e.g., cell adhesion and migration and adaptive im- munity [74-79]. The PVR has four main AS isoforms: i.e., α, Previous studies have shown that IL-33 plays a role in β, γ, and δ. The α and δ isoforms are transmembrane PVRs tumor promotion and inhibition, depending on the tumor (tm PVR) due to the existence of a transmembrane sequence type, targeted immune cells, and cytokines (Fig. 3). In breast encoded by exon 6. The other two isoforms are soluble PVRs cancer, IL-33 promotes tumor growth and metastasis [88]. (s PVR), which lack a transmembrane domain (Table 1) [80, For example, overexpression of IL-33 in ER+ human breast cancer cell lines can induce resistance to tamoxifen through 81]. Transmembrane PVRs function as active regulators of stem cell properties [89]. However, IL-33 can also reduce the CTL binding to membrane-located CD226 [82]. For exam- growth and metastatic ability of breast cancer as it maintains ple, hepatocellular carcinoma (HCC) escapes immune sur- a favorable microenvironment for cooperation between veillance by reducing the expression of transmembrane CD8+ T and NK cells to help eliminate tumors [90]. In colo- PVRs [78]. Soluble PVRS is highly expressed in serum in rectal cancer (CRC), IL-33 performs two opposite roles: i.e., tumor patients, including those with lung, gastrointestinal, promotion of tumor formation, proliferation, and metastasis breast, or gynecological cancer, resulting in the inhibition of [91, 92] and protection through IFN-γ-mediated anti-tumor the CTL anti-tumor immune response [83]. However, the immunity [93]. The dual role of IL-33 has also been found in ligands that bind to soluble PVRs remain to be clarified. lung cancer [87, 94]. PVR not only functions as an immune regulator, but its IL-33 possesses three mRNA transcript variants through ligands expressed in CTLs also play controversial roles. For AS [87]. Several studies have suggested that the multi- example, TIGIT serves as an inhibitory ligand of PVR and functions of IL-33 are related to its three isoforms (i.e., vari- dominates immunosuppression compared to CD226 (activa- ant 1: NM_001314044.1; variant 2: NM_001199640.1; vari- tor); furthermore, TIGIT+ CD226- CTLs occur in melano- ant 3: NM_001199641.1) (Table 1) [87]. For example, Af- ma, indicating a suppressive immune state [84]. However, ferni et al. [87] extracted data from ISO Expresso [95] and whether the competitive effect between TIGIT and CD226 is revealed that the expression levels of IL-33 variants 2 and 3 associated with different PVR isoforms remains unclear. increase in thyroid, liver, breast, and bladder cancers, where- Importantly, clinical trials (NCT01491893) [85] suggest that as the only variant 1 is expressed in normal tissues. This in- the genetically modified poliovirus vaccine may be a promis- dicates that specific abnormal splicing of IL-33 may be asso- ing cancer treatment. ciated with the progression of these tumors. The Roles of Alternative Splicing in Tumor-immune Cell Interactions Current Cancer Drug Targets, 2020, Vol. 20, No. 10 735

3.2. B Cells in Hematological Cancers challenges, screening new AS-based antigens as targets of immunotherapy will benefit tumor patients [111]. In addi- Diffuse large B cell lymphoma (DLBCL) is the most tion, specific AS events and their roles in immunity regula- common type of non-Hodgkin's lymphoma. Forkhead tran- tion need careful classification. Promisingly, the generation scription factor (FOXP1) is a potential oncogene in various of Spinraza, a drug for spinal muscular atrophy (SMA), high- types of cancer [96]. The N-terminal 100 amino acids of lights the possibility of splicing as a therapeutic target. FOXP1 are absent in the small isoform (FOXP1ΔN100) but not ΔN100 Spinraza is an antisense oligonucleotide, which plays a ther- in the full-length isoform [97]. FOXP1 is encoded by apeutic role by targeting the splicing of pre-SMN2 mRNA to FOXP1 mRNA lacking exon 6, resulting in translation start- ΔN100 increase the production of the full-length SMN protein [112]. ing from exon 8 (Table 1). FOXP1 is highly expressed With increasing research on the molecular functions of genes in DLBCL patients and predominantly activates B cells, thus and proteins with abnormal AS, more potential immunother- contributing to the development of DLBCL [98]. These in- apeutic targets of AS will emerge [113]. sights illustrate the high value of FOXP1 in assessing prog- nosis and treatment strategies for DLBCL patients. AS defects are often found in human cancers. They may be caused by a mutation in splicing regulatory elements of specific cancer genes or abnormal alteration of splicing 4. DISCUSSION events. RNA splicing regulators have emerged as a new class Based on a review of recent literature, AS appears to of oncoproteins and tumor suppressors that can regulate the serve as a double-edged sword in the regulation of tumor RNA isoforms involved in cancer hallmarks. In addition, AS immunity. Abnormal variant ULBP1 in tumor cells can acti- is a comprehensive and dynamic process rather than a static vate NK cells and thus has a killing effect on tumors, where- one. Thus, under clinical treatment application, how to target as abnormal variants of NCRs from NK cells can inhibit the AS events or splicing regulators effectively in order to pro- activation of NK cells and allow tumors to escape. Even dif- duce stable treatment, is worth further exploration. ferent isoforms produced by the same mRNA can have the opposite effects (e.g., IL-33); therefore, AS can be a weapon CONCLUSION used by both tumor cells and immune cells. We systematically elucidated the splicing events of sev- Many clinical applications target AS for therapeutic pur- eral specific genes that promote or inhibit tumors between poses. For example, tumors with deletion of exon 14 show tumor-immune cell interactions. We analyzed the innate and high sensitivity to the MET inhibitor [99, 100]. A similar adaptive immune responses of a variety of tumors, including example of BRAF V600E in melanomas has been also re- solid and hematologic tumors. Cancer-specific antigens pro- ported [101]. Furthermore, small molecules designed to duced by AS exhibit considerable potential in the develop- regulate RNA splicing have achieved good results in preclin- ment of novel therapeutic approaches for the treatment of ical studies. For example, Salton et al. reported a compre- cancers. hensive collection of AS-targeted small molecule. Gene-modified human polioviruses have been shown to AUTHOR CONTRIBUTIONS be effective in targeting PVR-positive tumor cells [77, 102- 104]. Furthermore, there are many proposed patents for AS Honglei Zhang, Jianyun Nie and Baowei Jiao designed and cancer [105]. For example, a new Bax isoform (Bax∆2) and supervised the work. Yue Wang and Honglei Zhang has been reported in colon cancer cell lines. Bax ∆2 can im- wrote the manuscript. Yue Wang created the three illustra- pair cancer cell sensitivity to chemotherapeutic drugs that tions for this manuscript. Xiyin Li, Wenhuan Wang and target caspase 8 [106]. Antibodies against Bax ∆2 can be Hairui Wang retrieved literature and analyzed the data. All used to detect Bax ∆2 expression levels in circulating tumor authors read and approved the final manuscript. cells isolated from patients, which is helpful for guiding clin- ical treatment strategies [106]. LIST OF ABBREVIATIONS Tumor immunology is an emerging field that has revolu- A3SS = Alternative 3’ splice sites tionized cancer treatment. Most immunotherapy strategies have focused on T cell engineering [107]. However, research A5SS = Alternative 5’ splice sites on NK cells has gradually increased, with such cells demon- AML = Acute myeloid leukemia strating a direct killing effect on tumor cells, without relying on specific antigen recognition [108]. Thus, NK cells exhibit APC = Antigen-presenting cells efficient elimination of distal metastasis and circulating tu- AS = Alternative splicing mor cells. In addition, the importance of macrophages in immunotherapy should not be ignored. For example, our ATF = Activating transcription factor previous study showed that extensive mutual AS editing ex- CD200L = Full-length CD200 ists between macrophages and breast cancer cells [109]. CD200R = CD200 receptor Taken together, we discussed the tumor-immune cell CD200S = Truncated forms of CD200 crosstalk from an AS point-of-view. As AS events produce many more recurrent neoantigens than are produced by point CGAs = Cancer germline antigens mutations [110], greater attention should be paid to AS- CRC = Colorectal cancer derived neoantigens. Although immunotherapies targeting AS-derived neoantigens face technological and biological CTL = Cytotoxic T lymphocytes 736 Current Cancer Drug Targets, 2020, Vol. 20, No. 10 Wang et al.

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